Exfoliative toxin A (ETA) secreted by Staphylococcus aureus causes destruction of human epidermis in bullous impetigo and Staphylcoccal Scalded Skin Syndrome (SSSS), which renders victims vulnerable to life-threatening infections and dehydration. Desmosomes are crucial for cell:cell adhesion in tissues enduring stress, such as the epidermis. These protein complexes anchor intermediate filaments to celhcell junctions, providing the mechanical strength necessary for the skin to serve as the body's first line of defense against environmental insults. Previous work has shown that ETA cleaves desmoglein 1 (Dsg1), a desmosome component and the predominant cadherin of the superficial epidermis. The proposed research will determine the specific molecular consequences of Dsg1 cleavage by ETA that contribute to SSSS. In particular, the toxin's effects on trafficking of and interactions among desmosomal components will be investigated as mechanisms reducing adhesion in keratinocytes; as well, a decoy Dsg1 ectodomain will be evaluated as an ETA inhibitor in vitro and in epidermal equivalents. The results will provide a more complete understanding of SSSS pathogenesis and will identify novel therapeutic targets for treatment of a toxin-mediated disease.